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Background: The toxic oil syndrome (TOS) epidemic that occurred in Spain in the spring of 1981 caused approximately 20000 cases of a new illness. Overall mortality and mortality by cause in this cohort through 1994 are described for the first time in this report.Methods: We contacted, via mail or telephone, almost every living member of the cohort and family members of those who were known to have died in order to identify all deaths from 1 May 1981 through 31 December 1994. Cause of death data were collected from death certificates and underlying causes of death were coded using the International Classification of Diseases, 9th Revision.Results: We identified 1663 deaths between 1 May 1981 and 31 December 1994 among 19 754 TOS cohort members, for a crude mortality rate of 8.4%. Mortality was highest during 1981, with a standardized mortality ratio (SMR) of 4.92 (95% confidence interval [CI]: 4.39-5.50) compared with the Spanish population as a whole. The highest SMR, (20.41, 95% CI: 15.97-25.71) was seen among women aged 20-39 years during the period from 1 May 1981 through 31 December 1982. Women <40 years old, who were affected by TOS , were at greater risk for death in most time periods than their unaffected peers, while older women and men were not. Over the follow-up period, mortality of the cohort was less than expected when compared with mortality of the general Spanish population, or with mortality of the population of the 14 provinces where the epidemic occurred. We also found that, except for deaths attributed to external causes including TOS and deaths due to pulmonary hypertension, all causes of death were decreased in TOS patients compared to the Spanish population. The most frequent underlying causes of death were TOS, 350 (21.1%); circulatory disorders, 536 (32.3%); and malignancies, 310 (18.7%).Conclusions: We conclude that while on average people affected by toxic oil syndrome are not at greater risk for death over the 13-year study period than any of the comparison groups, women <40 years old were at greater risk of death. [ABSTRACT FROM AUTHOR]

Objective: The abuse of prescription drugs has increased dramatically since 1990. Persons who overdose on such drugs frequently consume large doses and visit multiple providers. The risk of fatal overdose for different patterns of use of opioid analgesics and sedative/hypnotics has not been fully quantified., Design: Matched case-control study. Cases were 300 persons who died of unintentional drug overdoses in New Mexico during 2006-2008, and controls were 5,993 patients identified through the state prescription monitoring program with matching 6-month exposure periods., Outcome Measures: Death from drug overdose or death from opioid overdose. Exposures were demographic variables and characteristics of prescription history. Crude and adjusted odds ratios (AOR) were calculated., Results: Increased risk was associated with male sex (AOR 2.4, 95% confidence interval [CI] 1.8-3.1), one or more sedative/hypnotic prescriptions (AOR 3.0, CI 2.2-4.2), greater age (AOR 1.3, CI 1.2-1.4 for each 10-year increment), number of prescriptions (AOR 1.1, CI 1.1-1.1 for each additional prescription), and a prescription for buprenorphine (AOR 9.5, CI 3.0-30.0), fentanyl (AOR 3.5, CI 1.7-7.0), hydromorphone (AOR 3.3, CI 1.4-7.5), methadone (AOR 4.9, CI 2.5-9.6), or oxycodone (AOR 1.9, CI 1.4-2.6). Patients receiving a daily average of >40 morphine milligram equivalents had an OR of 12.2 (CI 9.2-16.0)., Conclusions: Patients being prescribed opioid analgesics frequently or at high dosage face a substantial overdose risk. Prescription monitoring programs might be the best way for prescribers to know their patients' prescription histories and accurately assess overdose risk., (Wiley Periodicals, Inc.)

Objective: Drug overdoses resulting from the abuse of prescription opioid analgesics and other controlled substances have increased in number as the volume of such drugs prescribed in the United States has grown. State prescription drug monitoring programs (PDMPs) are designed to prevent the abuse of such drugs. This study quantifies the relation of PDMPs to rates of death from drug overdose and quantities of opioid drugs distributed at the state level., Design: Observational study of the United States during 1999-2005., Outcome Measures: Rates of drug overdose mortality, opioid overdose mortality, and opioid consumption by state., Results: PDMPs were not significantly associated with lower rates of drug overdose or opioid overdose mortality or lower rates of consumption of opioid drugs. PDMP states consumed significantly greater amounts of hydrocodone (Schedule III) and nonsignificantly lower amounts of Schedule II opioids. The increases in overdose mortality rates and use of prescription opioid drugs during 1999-2005 were significantly lower in three PDMP states (California, New York, and Texas) that required use of special prescription forms., Conclusions: While PDMPs are potentially an important tool to prevent the nonmedical use of prescribed controlled substances, their impact is not reflected in drug overdose mortality rates. Their effect on overall consumption of opioids appears to be minimal. PDMP managers need to develop and test ways to improve the use of their data to affect the problem of prescription drug overdoses., (Wiley Periodicals, Inc.)

Since September 11, 2001, concern about potential terrorist attacks has increased in the United States. To reduce morbidity and mortality from outbreaks of illness from the intentional release of chemical agents, we examine data from the Toxic Exposure Surveillance System (TESS). TESS, a national system for timely collection of reports from US poison control centers, can facilitate early recognition of outbreaks of illness from chemical exposures. TESS data can serve as proxy markers for a diagnosis and may provide early alerts to potential outbreaks of covert events. We use 3 categories of information from TESS to detect potential outbreaks, including call volume, clinical effect, and substance-specific data. Analysis of the data identifies aberrations by comparing the observed number of events with a threshold based on historical data. Using TESS, we have identified several events of potential public health significance, including an arsenic poisoning at a local church gathering in Maine, the TOPOFF 2 national preparedness exercise, and contaminated food and water during the northeastern US blackout. Integration of poison control centers into the public health network will enhance the detection and response to emerging chemical threats. Traditionally, emergency physicians and other health care providers have used poison control centers for management information; their reporting to these centers is crucial in poisoning surveillance efforts.

In 1981, in Spain, the ingestion of an oil fraudulently sold as olive oil caused an outbreak of a previously unrecorded condition, later known as toxic oil syndrome (TOS), clinically characterized by intense incapacitating myalgias, marked peripheral eosinophilia, and pulmonary infiltrates. Of the 20,000 persons affected, approximately 300 died shortly after the onset of the disease and a larger number developed chronic disease. For more than 15 years, a scientific committee supported by the World Health Organization's Regional Office for Europe and by the Institute of Health Carlos III in Madrid has guided investigation intended to identify the causal agent(s), to assess toxicity and mode of action, to establish the pathogenesis of the disease, and to detect late consequences. This report summarizes advances in research on this front. No late mortality excess has been detected. Among survivors, the prevalence of some chronic conditions (e.g., sclerodermia, neurologic changes) is high. Attempts to reproduce the condition in laboratory animals have been unsuccessful, and no condition similar to TOS has been reported in the scientific literature. Laboratory findings suggest an autoimmune mechanism for TOS, such as high levels of seric soluble interleukin-2 receptor. Epidemiologic studies integrated with chemical analyses of case-related oils have shown that the disease is strongly associated with the consumption of oils containing fatty acid esters of 3-(N-phenylamino)-1,2-propanediol (PAP). These chemicals have also been found in oils synthesized under conditions simulating those hypothesized to have occurred when the toxic oil was produced in 1981. Whether PAP esters are simply markers of toxicity of oils or have the capability to induce the disease remains to be elucidated.

Development of effective public health information systems requires understanding public health informatics (PHI), the systematic application of information and computer science and technology to public health practice, research, and learning. PHI is distinguished from other informatics specialties by its focus on prevention in populations, use of a wide range of interventions to achieve its goals, and the constraints of operating in a governmental context. The current need for PHI arises from dramatic improvements in information technology, new pressures on the public health system, and changes in medical care delivery. Application of PHI principles provides unprecedented opportunities to build healthier communities.

Toxic oil syndrome appeared in epidemic form in Spain in 1981. Epidemiologic studies have demonstrated that illness was caused by consumption of rapeseed oil that had been denatured with aniline. Chemical analyses of oil specimens conducted in conjunction with epidemiologic studies have established that consumption of specific oils containing fatty acid anilide contaminants was associated with increased risk for disease. New chemical analytic methods identified a family of compounds, the di-fatty acid esters of phenylamino propane-diol, and one of these compounds, the 1,2-di-oleyl ester of 3-(N-phenylamino)-1,2-propanediol (DPAP), has been found to be more strongly associated with disease status than the fatty acid anilides. We found the odds ratio for exposure to DPAP (OR = 26.4, 95% CI = 6.4-76.3) is much higher than the odds ratio for exposure to oleyl anilide (OR = 4.1, 95% CI = 2.2-7.8), implying that exposure to DPAP was a more relevant risk factor for development of toxic oil syndrome than exposure to oleyl anilide. In this paper, we review and present analyses of data from multiple studies of the possible etiologic role of DPAP in toxic oil syndrome. The presence of DPAP in oil collected from affected and unaffected households was a more specific correlate of case relatedness than was the presence of fatty acid anilides, and it was equally sensitive. Moreover, DPAP was found in oil from the only refinery whose oil was clearly associated with illness.

Evidence from an array of scientific studies strongly supports the conclusion that ingestion of products containing L-tryptophan (LT) produced by Showa Denko KK caused the 1989 epidemic of eosinophilia-myalgia syndrome (EMS) in the United State. In case-control studies of EMS, LT exposure was essentially universal among cases but rare among controls. Of 6 manufacturers of LT, only LT manufactured by Showa Denko KK was clearly associated with illness. The data meet other Hill criteria for inferring a causal relationship. Consistent findings were found in multiple independently conducted studies. There was a dose-response effect, with risk of illness increasing as a function of the amount of tryptophan consumed. The extremely small p values observed in the multiple independently conducted studies effectively rule out the possibility that the tryptophan-EMS association was the result of chance. Moreover, no potential confounding factor or bias explains the association. The incidence of EMS in the United States diminished abruptly once LT containing products were recalled.

Rapeseed oil denatured with aniline was the vehicle of the causal agent of the toxic oil syndrome (TOS) epidemic that occurred in Spain in 1981. Although the precise aetiologic agent remains unknown, researchers established that increasing concentrations of oleyl anilide and other fatty acid anilides were associated with an increased risk for disease. To examine the hypothesis that 5-litre plastic containers of rapeseed oil associated with TOS, and which contained oleyl anilide had a characteristic shape, we measured fatty acid, sterol and fatty acid anilide levels in oil from containers of different shapes. We identified 1673 bottles of oil that had been collected during the Spanish Government's oil exchange programme and linked these bottles to people with TOS as reported in the official government census of patients with TOS. Although rapeseed oil (identified by the presence of brassicasterol) was found in 798 (47.7%) of the 1673 bottles examined, contamination with fatty acid anilide occurred in only 329 (19.6%) of the 1673 bottles and 319 (97%) of the 329 were oil containers of the shape sold by RAELCA, an oil company in Madrid. The first aniline-denatured oil that RAELCA had purchased to be refined specifically for distribution was refined at the ITH refinery of Seville, and this oil has been most directly associated with the epidemic. Previous work has shown that the only toxic oil linked to a specific refinery was that associated with rapeseed oil from the ITH refinery in Seville, and the epidemic began shortly after this oil was delivered to RAELCA for retail sale. On the basis of these findings, we conclude that oil refined by ITH and distributed by RAELCA was the principal, and probably the only, oil responsible for the TOS epidemic. Information about the history and treatment of this oil may yield important clues towards identifying the aetiologic agent of TOS.

The etiologic agent(s) that was responsible for the 1981 toxic oil syndrome [TOS] epidemic in Spain has not been identified. Liquid chromatography combined with atmospheric pressure ionization tandem mass spectrometry was used for the analysis of oils associated with TOS. Analyses focused on measuring 3-(N-phenylamino)-1,2-propanediol [PAP], the 3-oleyl ester of PAP [MEPAP], and the 1,2-di-oleyl ester of PAP [DEPAP]. DEPAP and MEPAP were found more frequently and at higher concentrations in TOS case-associated oils than in control oils with odds ratios of 13.7 (95% CI 5.0-38) and 21.9 (95% 6.1-78), respectively. Other fatty acid esters of PAP are also likely to be present in the TOS case-associated oils. More significantly, DEPAP and MEPAP were found in aniline-denatured rapeseed oil refined at ITH, the oil refining company with the clearest link to TOS cases, yet these PAP esters were not detected in unrefined aniline-denatured samples of rapeseed oil delivered to ITH. These results show that the esters of PAP were products of the ITH refining process and were not formed spontaneously during storage. PAP esters were not detected in samples of other aniline-denatured rapeseed oils that were refined elsewhere, and which were not associated with illness. These findings provide strong support for the hypothesis that one or more of the fatty acid esters of PAP were the etiologic agents for TOS.

The authors conducted a mailed questionnaire survey of a 5% sample of the cohort of 20,643 people officially recognized by the Spanish government as having had toxic oil syndrome, a previously undescribed illness that was epidemic in Spain in 1981. After three mailings of a letter and questionnaire, responses for only 66% of the sample had been received. Nevertheless, responses were obtained from virtually all remaining patients (or surrogates for them in the cases of patients that had died) when they were sought by telephone. In 1981, there was clear-cut excess mortality in the cohort (standardized mortality ratio [SMR] 6.51; 95% confidence interval [CI]: 3.92-10.17). During the period January 1982 through 7 March 1988, there was no statistically significant overall mortality excess except during the period 1982-1983 among people aged < 65 years (SMR 2.26; 95% CI: 1.03-4.29). Toxic oil syndrome substantially altered the patterns of mortality among affected people. Analysis of deaths by cause among the TOS cohort will be useful for further evaluation of the long-term impact of the TOS epidemic.

Eosinophilia-myalgia syndrome (EMS) has been linked to ingestion of tryptophan contaminated with 1,1'-ethylidene-bis[L-tryptophan] (EBT), but other contaminants have received little study. The authors identified 101 lots of L-tryptophan that had been consumed either by persons with EMS or by asymptomatic tryptophan users and quantified the amounts of EBT and five other contaminants in each lot. After stratification of case and noncase lots by time of manufacture to adjust for the strong sequential pattern over time among case and noncase lots, higher EBT levels were still associated with a lot's case status, but the association lacked statistical significance (p = 0.120, odds ratio = 1.56, 95% confidence interval 0.758-3.23). While these findings do not rule out the possibility that EBT is the etiologic agent in EMS, they raise the possibility that other chemical contaminants in manufactured tryptophan modify the effects of EBT or that the causal agent of EMS is an entirely distinct compound.

In late October 1989, over 1,500 cases of an unusual illness involving severe myalgia and striking peripheral eosinophilia were reported in the United States and several other countries. Other clinical manifestations included pulmonary involvement (interstitial infiltrates and pleural effusions), skin rash and edema, axonal polyneuropathy, perimyositis, and possible adverse neurocognitive effects. Because of the primary manifestations of the illness, it was named "eosinophilia-myalgia syndrome" (EMS) by the Centers for Disease Control. Epidemiologic studies clearly linked illness to the ingestion of tryptophan produced by a single manufacturer in Japan, and the time course of the epidemic was most consistent with its being caused by a product contaminant. Epidemiologic analysis of plant operating conditions and data obtained from chemical analyses of case- and control-associated lots implicated 1,1'-ethylidene-bis(tryptophan) (EBT) as a candidate for the compound that causes EMS. However, the etiologic significance of EBT is still uncertain. Factors found to increase a person's risk for EMS included higher tryptophan dose and older age. Although cases occurred predominantly in women and patients had frequently been taking other medications concurrently with tryptophan, sex and use of several categories of other medications were not shown to influence the risk of illness. Few patients recovered rapidly and fully from the disease. Many were treated with glucocorticoid medications, and although they may have benefited from therapy in the short term, the development of chronic sequelae of EMS appears not to have been prevented. Public health practitioners currently depend on the reports of alert clinicians to detect this type of outbreak. In this case, state and federal government epidemiologists, once they were notified, were able to develop substantial basic information about the epidemic in a relatively short time. Control measures were introduced rapidly, effectively stopping the epidemic.

Objectives: To study the incidence of eosinophilia-myalgia syndrome, the risk factors associated with the syndrome, and the clinical spectrum of illness associated with L-tryptophan use in an exposed population., Design: Retrospective cohort and nested case-control studies of risk factors for eosinophilia-myalgia syndrome using inpatient and outpatient chart reviews, telephone interviews, and in-person patient interviews. Descriptive study of clinical course of L-tryptophan users., Setting: Office practice of one psychiatrist based in a small city (population 43,467) in South Carolina., Patients: Eligible subjects were all patients from the practice who used L-tryptophan during the 1989 study interval. Of these, 418 (87%) were interviewed., Main Outcome Measures: Clinical spectrum of illness associated with L-tryptophan use, including definite and possible cases of eosinophilia-myalgia syndrome., Results: Among the 418 interviewed L-tryptophan users, we identified 47 definite cases (11%) and 68 possible cases (16%) of eosinophilia-myalgia syndrome, most of which involved patients who were using one retail brand of L-tryptophan (brand A). Among the 157 brand A users, we identified 45 definite cases (29%) and 36 possible cases (23%) of eosinophilia-myalgia syndrome, and the risk for the syndrome increased as the brand A dose increased. Fifty percent (19 of 38) of those using more than 4000 mg/day developed definite eosinophilia-myalgia syndrome, and 84% (32 of 38) developed either definite or possible eosinophilia-myalgia syndrome. On multivariate analysis, risk for definite eosinophilia-myalgia syndrome was associated with brand A dose and age of the patient; however, gender, race, and use of other medications were not associated with the syndrome., Conclusions: These results suggest that many people exposed to the agent causing eosinophilia-myalgia syndrome may develop illness, and dose of presumably contaminated L-tryptophan is the single most important predictor of eosinophilia-myalgia syndrome. The broad range of signs and symptoms reported by patients using L-tryptophan illustrates that a strict case definition may identify only about half of those affected.

The toxic oil syndrome (TOS) epidemic that occurred in Spain in spring 1981 has been associated with the consumption of rapeseed oil that was denatured with aniline for industrial use but diverted for human consumption. The precise aetiologic agent in the oil responsible for the outbreak has not been identified. To learn more about possible contaminants and how the contamination might have occurred, we visited two French companies that process rapeseed oil and that were identified in Spanish administrative and judicial records as the ones exporting aniline-denatured rapeseed oil to Spain in 1981. With the apparently full and voluntary co-operation of personnel at both companies, we reviewed the processes involved in manufacturing, treating and transporting rapeseed oil, and we have summarized the information provided to us. Of particular importance is the finding that oil exported to Spain was taken from stock, the rest of which was sold for human consumption in the French domestic market, apparently without any adverse health effects. The differences between the oil exported to Spain and the oil sold as food in France were that aniline equivalent to 2% of the weight of the oil was added to most of the Spanish oil but not to that sold in France, and that contamination of the Spanish oil may have occurred in the tank trucks used for transportation to Spain, which had previously carried industrial chemicals. There is no assurance that the trucks were cleaned appropriately for transporting a food product before the oil was loaded for the journey to Spain. Since the clinical manifestations of TOS are not those of aniline toxicity, we conclude that the aetiological agent of TOS is likely to be one of the following: (1) a contaminant in the aniline, (2) a contaminant introduced during transportation, (3) a reaction product of normal oil components or materials used in refining with either aniline or the potential contaminants mentioned under (1) or (2) above.

In the spring and summer of 1981, an epidemic of a new illness now referred to as the toxic oil syndrome occurred in central and northwestern Spain, resulting in some 20,000 cases, 12,000 hospital admissions and greater than 300 deaths in the 1st year of the epidemic. The initial onset of illness was usually acute, and patients presented primarily with a respiratory syndrome involving cough, fever, dyspnea, hypoxemia, pulmonary infiltrates and pleural effusions. While approximately 50% of patients recovered from this acute phase of the illness without apparent sequelae, the remaining patients developed an intermediate or chronic phase, or both, of illness involving severe myalgia, eosinophilia, peripheral nerve damage, sclerodermiform skin lesions, sicca syndrome, alopecia and joint contractures, among other findings. Epidemiologic and analytic chemical studies have clearly linked the toxic oil syndrome to the ingestion of oil mixtures containing rapeseed oil denatured with aniline. However, the precise identity of the etiologic agent within this oil has never been determined. Aniline itself did not cause the illness, but the causal agent may be a reaction product of aniline with some oil component. Although many aspects of disease activity in the involved patients have lessened with time, the ultimate consequences of their disease are not clear and are the subject of ongoing study. The recently described eosinophilia-myalgia syndrome in the United States clinically resembles the toxic oil syndrome.

Objective: To examine the hearts of individuals who died from the eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan, with particular attention paid to the coronary arteries, the neural structures, and the conduction system of the heart because of reported terminal disturbances of cardiac rhythm and conduction., Study Material: Three hearts fixed in neutral formalin and well preserved with all the relevant areas of conduction system intact., Methods: Light microscopic examination of subserial sections of the sinus node, atrioventricular node and His bundle, coronary chemoreceptor and regional nerves, ganglia, and small coronary arteries. Routine stains used were Goldner trichrome and Verhoeff-van Gieson., Results: Arterial abnormalities were numerous and primarily of two types: focal fibromuscular dysplasia causing moderate to severe narrowing, as well as endarteritis and panarteritis. Extensive examples of neuritis and ganglionitis were present throughout the heart, including the conduction system, where arterial abnormalities were also abundant. In the coronary chemoreceptor there were both old and new lesions comprising focal inflammation with degeneration as well as older areas of fibrotic destruction. Within the sinus node, areas of dense fibrosis replaced all nodal tissue. These abnormalities were similar in nature and extent in all three hearts., Conclusions: The pathologic lesions present in the coronary arteries, neural structures, and conduction system of the heart in patients who died from the eosinophilia-myalgia syndrome provide a suitable anatomic substrate for substantial cardiac electrical instability, including the occurrence of sudden death. In cases of unexplained cardiac electrical instability or sudden unexpected death an inquiry should be made about previous use of L-tryptophan. In patients with the eosinophilia-myalgia syndrome, the possibility of cardiac electrical instability should be considered as part of long-range clinical management.

We reviewed 21 cases of eosinophilia-myalgia syndrome to describe the range of clinical findings in these patients. Most patients were women (20 [95%]) and middle-aged (mean, 46 years) and had taken the food supplement L-tryptophan (95%). All cases involved eosinophilia (eosinophil count, greater than or equal to 2.0 x 10(9)/L) and incapacitating myalgias. Fourteen (88%) of the 16 patients tested had mild liver function abnormalities. Aldolase levels were abnormal in all patients tested. Muscle biopsies were done in five patients; four showed eosinophilic perimyositis, and one had interstitial inflammation. No physical finding was pathognomonic or universal, but muscle tenderness, tachycardia, and rash were the most common signs found during physical examinations. Seven patients were treated with prednisone, and six showed improvement in muscle pain and a decrease in eosinophilia. The cause of this disorder is still unknown.

The participation of eosinophils in the Spanish toxic oil syndrome (TOS) was investigated. Eosinophil infiltration and degranulation in tissues from 52 patients with the TOS were examined by immunofluorescence staining for the eosinophil granule major basic protein (MBP). Serum MBP levels were determined in sera from 323 patients. Eosinophil infiltration and degranulation were found in several tissues, especially during the acute phase of the TOS, and serum MBP was significantly elevated during all phases of the disease, suggesting that eosinophils play a role in the pathogenesis of the TOS.

Background: Many paint companies have used phenylmercuric acetate as a preservative to prolong the shelf life of interior latex paint. In August 1989, acrodynia, a form of mercury poisoning, occurred in a child exposed to paint fumes in a home recently painted with a brand containing 4.7 mmol of mercury per liter (at that time the Environmental Protection Agency's recommended limit was 1.5 mmol or less per liter)., Methods: To determine whether the recent use of that brand of paint containing phenylmercuric acetate was associated with elevated indoor-air and urinary mercury concentrations, we studied 74 "exposed" persons living in 19 homes recently painted with the brand and 28 "unexposed" persons living in 10 homes not recently painted with paint containing mercury., Results: The paint samples from the homes of exposed persons contained a median of 3.8 mmol of mercury per liter, and air samples from the homes had a median mercury content of 10.0 nmol per cubic meter (range, less than 0.5 to 49.9). No mercury was detected in paint or air samples from the homes of unexposed persons. The median urinary mercury concentration was higher in the exposed persons (4.7 nmol of mercury per millimole of creatinine; range, 1.4 to 66.5) than in the unexposed persons (1.1 nmol per millimole; range, 0.02 to 3.9; P less than 0.001). Urinary mercury concentrations within the range that we found in exposed persons have been associated with symptomatic mercury poisoning., Conclusions: We found that potentially hazardous exposure to mercury had occurred among persons whose homes were painted with a brand of paint containing mercury at concentrations approximately 2 1/2 times the Environmental Protection Agency's recommended limit.

Eosinophilia-myalgia syndrome, a newly recognized disorder that occurred in epidemic proportions during 1989, is associated with ingestion of manufactured tryptophan. A case is defined by debilitating myalgias and absolute eosinophilia greater than or equal to 1.0 x 10(9) cells/L. As of July 10, 1990, a total of 1531 cases had been reported nationwide, including 27 deaths. The highest rates of reported illness are concentrated in the western states, 68% are non-Hispanic white women aged 35 years and older, and data on associated clinical findings suggest a multisystemic disorder. The most frequent features include arthralgia (73%), rash (60%), cough or dyspnea (59%), peripheral edema (59%), elevated aldolase level (46%), and elevations in the results of liver function tests (43%). Neuropathy or neuritis, resulting in paralysis and death in some patients, was seen in 27%, and chest roentgenogram abnormalities were noted in 21% of those tested. Ninety-one percent reported onset of symptoms during or after May 1989, and 97% reported having taken tryptophan before the onset of symptoms. Since the recall of over-the-counter preparations of tryptophan in November 1989, the number of new cases of this potentially fatal disorder has fallen dramatically.

On Oct 30, 1989, the New Mexico Health and Environment Department learned of 3 patients with eosinophilia and severe myalgia who had been taking L-tryptophan. Further review of these and similar cases led to the initial recognition of the eosinophilia-myalgia syndrome (EMS) epidemic. To elucidate the apparent association between L-tryptophan-containing products (LTCPs) and EMS a case-control study was done. The case definition was unexplained peripheral eosinophilia (2000/microliters or more) and incapacitating myalgia. Cases were found through review of white blood cell counts from May 1 to Oct 31, 1989, in nine medical laboratories in New Mexico. 11 cases and 22 matched controls were interviewed for information on symptoms and other clinical findings, on the use of LTCPs, and on potential confounding factors. All 11 cases (100%) used LTCPs compared with only 2 controls. These findings led to a ban on the sale of LTCPs in New Mexico, followed by a nationwide recall of such preparations in the United States.

An outbreak of paralytic shellfish poisoning occurred in Champerico, on the Pacific coast of Guatemala, July-August 1987. Of 187 people affected with characteristic neurologic symptoms, 26 died. A case study implicated a species of clam, Amphichaena kindermani, harvested from local beaches as the vehicle of the neurotoxins (saxitoxins). Children less than 6 years old had a higher fatality rate (50%) than people greater than 18 years of age (7%). The minimum lethal dose for 1 child was estimated to have been 140 mouse units of toxin/kg body weight; thus children may be more sensitive to the saxitoxins than are adults. This is the first large outbreak of paralytic shellfish poisoning recognized in Guatemala.

The morbidity and mortality associated with the 1980 heat wave in St Louis and Kansas City, Mo, were assessed retrospectively. Heat-related illness and deaths were identified by review of death certificates and hospital, emergency room, and medical examiners' records in the two cities. Data from the July 1980 heat wave were compared with data from July 1978 and 1979, when there were no heat waves. Deaths from all causes in July 1980 increased by 57% and 64% in St Louis and Kansas City, respectively, but only 10% in the predominantly rural areas of Missouri. About one of every 1,000 residents of the two cities was hospitalized for or died of heat-related illness. Incidence rates (per 100,000) of heatstroke, defined as severe heat illness with documented hyperthermia, were 26.5 and 17.6 for St Louis and Kansas City, respectively. No heatstroke cases occurred in July 1979. Heatstroke rates were ten to 12 times higher for persons aged 65 years or older than for those younger than 65 years. The ratios of age-adjusted heatstroke rates were approximately 3:1 for nonwhite v white persons and about 6:1 for low v high socioeconomic status. Public health preventive measures in future heat waves should be directed toward the urban poor, the elderly, and persons of other-than-white races.

The authors studied the pattern of occurrence of toxic oil syndrome, a previously undescribed disease that occurred in Spain in epidemic form in 1981, in two convents in Madrid. In one convent, the disease affected 66% of 35 novices and nuns who ingested oil from a suspect source, but none of 56 laywomen who ate the same meals but used a different type of oil. In the second convent, in which nuns were also exposed but laywomen were not, 98% of 43 nuns developed toxic oil syndrome compared with none of 70 laywomen. These findings support the hypothesis that a food oil transmitted the etiologic agent of toxic oil syndrome.

Mapping is a useful tool for initiating data analysis of relatively infrequent injury events and can lead to interesting hypotheses that can then be tested in further epidemiologic studies. From national death certificate data for the years 1979 through 1985, we made dot maps of fatalities due to excessive heat (International Classification of Diseases code E900) among persons 65 years or older. The maps show clusterings of deaths, particularly in the central, south central, and southeastern sections of the United States, to an extent not fully explained by the population density or temperature extremes. The counties principally affected were highly urbanized and, for races other than white, were relatively poor. Our maps identify counties in which heat-related health problems in the elderly are particularly severe. Public health officials in high-risk areas should undertake heat-wave contingency planning and physicians practicing in such areas should familiarize themselves with the treatment of the spectrum of heat-related illnesses.

The symptoms of toxic oil syndrome (TOS), an epidemic that occurred in central and north-western Spain, developed in the great majority of patients during May or June 1981. We now describe the clinical and epidemiological data of five patients with TOS whose onset of symptoms was considerably later than the great majority of cases. In June 1982, one person became symptomatic as a result of consuming a suspect oil two months earlier. Four members of a family that started consuming a suspect oil in November 1981 became ill in December 1981. These data indicate that the aetiological agent of TOS persisted in stored oil for periods as long as one year. The apparent stability of the TOS aetiological agent increases the likelihood of its continued presence in significant concentrations in oils that have been stored since 1981. Thus, the use of such oils in further in vivo and in vitro toxicological studies may yet lead to the isolation and identification of the causal agent of TOS.

Toxic-oil syndrome (TOS), a new disease that occurred in epidemic form in Spain in 1981, has been associated with the ingestion of unlabelled oil bought principally from travelling salesmen. Chemical analysis of oils taken from ill families has shown them to consist of varying proportions of different vegetable oils and animal fats, often showing chemical evidence of prior treatment with aniline. We investigated the unusual circumstances surrounding the reported occurrence of three TOS cases in two families in Sevilla, a city located far away (approximately 300 km) from the group of 14 provinces in central and northwestern Spain where 99% of the TOS cases occurred. Each case we investigated fitted the clinical picture of TOS and was not consistent with any other diagnosis. Illness apparently occurred as a result of ingestion of oil taken from the ITH oil refinery in Sevilla, a plant in which rapeseed and grapeseed oils were refined for the distributing firm through which oil bearing the causative agent of TOS is thought to have entered the market. These data provide further strong support for the hypothesis that food oil was the vehicle by which the aetiological agent of TOS was transmitted. Because ingestion of refined denatured rapeseed oil was most closely associated with the illness in time, the TOS agent was probably contained initially in this type of oil. The agent very probably entered later oil mixtures through such contaminated rapeseed oil.

In a cluster of illness reported among students at an elementary school parents mentioned many signs and symptoms including headache, pallor, dark circles under the eyes, nausea, and vomiting--which they attributed to exposure to recurrent leaks of natural gas at the school. It is likely that the parents spread among themselves the notion of toxic exposure at the school. A questionnaire revealed no spatial clustering, but increased reports of symptoms were related to intense media coverage. A thorough environmental and epidemiological investigation was negative, there being no evidence of a continuing gas leak or other potential causes. At a strictly biological level, the complaints in this reported "cluster" apparently represented the sporadic occurrence of common childhood illnesses. The possibility of an epidemic from toxic exposure at the school caused intense parental concern and led to a major public health problem. The established term "mass sociogenic illness" seems inapplicable here because complaints did not come principally from the students and the apparent epidemic illness was not transmitted among them. The term "mass sociogenic illness by proxy" is proposed to describe this incident, in which transmission in one group (the parents) resulted in reports of an epidemic in another group (students).

To elucidate the aetiological role of food oil in toxic-oil syndrome (TOS), 212 families of a working class neighbourhood in Madrid were interviewed regarding the sources of food oil they consumed and whether they had become ill with TOS. Health information was later verified by review of the patients' medical records. All five case families consumed oil sold by travelling salesmen in five-litre plastic containers, but only 34% of the 207 non-case families did so (p = 0.005). Oil bought from travelling salesmen in the local weekly open-air market was associated with a particularly high risk of illness. Consumption of oil from sources other than travelling salesmen was similar in the two groups. Our results support the view that a food oil transmitted the causative agent of TOS.

The identity of the etiologic agent that caused the 1981 epidemic of toxic oil syndrome in Spain has not been established, and toxicologic study of oil specimens from the outbreak has been hampered by uncertainty about which oils were actually capable of causing illness. To identify chemical characteristics associated with pathogenicity, the authors compared specimens collected during the Spanish government's oil recall program in June and July 1981 from affected and unaffected households in the two contiguous towns of Alcorcón and Leganés (Madrid Province). Oils were blind-coded for laboratory analysis, and personnel with no knowledge of the laboratory results determined whether illness was present in a family. Contamination with free aniline and oleyl, linoleyl, and palmityl anilides was strikingly more frequent and extensive in oils collected from the case (affected) families. There was a clear-cut dose-response effect, with increasing concentrations of aniline and anilides associated with increasing risk of illness. Differences in fatty acid and sterol compositions among oils indicated more rapeseed oil admixture in the case group, but these indicators of rapeseed oil admixture did not contribute significantly to risk after the degree of aniline/anilide contamination had been taken into account. The authors conclude that the presence of relatively high levels of aniline and fatty acid anilides in oil specimens collected during the epidemic in the two towns studied indicates a high probability of the current or prior presence of the etiologic agent of toxic oil syndrome. Although these data do not necessarily indicate that any of the compounds measured actually caused the illness, further toxicologic work should concentrate on oils with substantial concentrations of the marker compounds.

An epidemic of a new illness involving multiple organ systems began in Spain in May 1981, with 19,828 cases and 315 deaths reported by June 1, 1982. An epidemiologic investigation has linked the occurrence of illness with ingestion of an unlabeled, illegally marketed cooking oil. To elucidate the natural history of this illness, we reviewed the medical records of 121 patients in one severely affected town 100 km northwest of Madrid. The findings during the first week after onset were those of a febrile, pneumonia-like illness. Gastrointestinal findings and striking eosinophilia became prominent later in the first month. Although the disease followed a self-limited course in many patients, severe neuromuscular manifestations (myalgia severe enough to restrict movement, motor deficits, atrophy of major muscle groups, and contractures of the jaw and extremities) occurred late in the course of the illness (an average of 96 days after onset) in 23 per cent of the patients. The onset of disease early in the epidemic and particularly severe initial systemic findings were associated with progression to neuromuscular illness.

To identify risk factors associated with heatstroke, a case-control study in St Louis and Kansas City, Mo, was conducted during July and August 1980. Questionnaire data were gathered for 156 persons with heatstroke (severe heat illness with documented hyperthermia) and 462 control subjects matched by age, sex, and neighborhood of residence. A stepwise linear logistic regression procedure was used to identify factors significantly associated with heatstroke. Alcoholism, living on the higher floors of multistory buildings, and using major tranquilizers (phenothiazines, butyrophenones, or thioxanthenes) were factors associated with increased risk. Factors associated with decreased risk were using home air conditioning, spending more time in air-conditioned places, and living in a residence well shaded by trees and shrubs. Being able to care for oneself, characteristically undertaking vigorous physical activity, but reducing such activity during the heat, and taking extra liquid were also associated with decreased risk. Our findings also suggest effective preventive measures. During a heat wave, the greatest attention should be directed toward high-risk groups, and relief efforts should include measures shown to be associated with reduced risk.

Previous reports have implicated 1-phenyl-5-vinyl imidazolidine-2-thione (PVIZT), a cyclic reaction product of aniline and naturally occurring rapeseed oil isothiocyanates, as the potential causative agent of the Spanish toxic oil syndrome (TOS). This report describes the synthesis, preliminary characterization and analysis of that reaction product, which has been identified as N-(5-vinyl-1,3-thiazolidin-2-ylidene)phenylamine (5-VTPA) rather than PVIZT. Oil samples (n = 21) that contained fatty acid anilides and were epidemiologically linked to TOS were analysed for the presence of 5-VTPA by extraction of the oil with methanol and clean-up on an ion-exchange column, followed by capillary gas chromatography-mass spectrometry using selected ion detection. A limit of detection of less than 500 ppb was established for these analyses. No 5-VTPA could be detected, however, in any of the TOS oils. As 5-VTPA was shown to be unstable in both heated and unheated food oils, it is possible that the compound had been lost from the oils since the time of the epidemic in 1981. However, no direct evidence for the involvement of 5-VTPA in TOS could be obtained in this study.

Serotonin injected in the left atrium activates a cardiogenic hypertensive chemoreflex in dogs. To elucidate patterns of the neural traffic, records were obtained from thoracic sympathetic efferent nerves (either the anterior ansa of the left stellate ganglion or the T4 input to the left stellate) in 8 anesthetized dogs with chest open. Serotonin (200 micrograms, left atrium) caused a massive sympathetic discharge during the hypertension and bracardia characteristic of the chemoreflex. Following the initial sympathetic discharge, there was a consistent post-excitatory depression of neural traffic, to a level significantly less than control discharge (two-tailed p less than .05). This post-excitatory depression began 11 +/- 5.4 (S.D.) seconds after injection of serotonin and 6.6 +/- 5.3 seconds after the peak neural discharge. It lasted 140 +/- 94 seconds, being maximal initially with gradual recovery. Complete block of the hypertension by the combined administration of phentolamine, propranolol, and nitroglycerin failed to abolish the efferent neural events, including post-excitatory depression, in all but one dog. We conclude that post-excitatory depression in thoracic sympathetic efferent neural traffic cannot be mediated exclusively through the secondary engagement of a baroreceptor mechanism and that it most likely is an integral part of the cardiogenic hypertensive chemoreflex.